Association of Systemic Lupus Erythematosus with C8orf13–BLK and ITGAM–ITGAX
Geoffrey Hom, Ph.D., Robert R. Graham, Ph.D., Barmak Modrek, Ph.D., Kimberly E. Taylor, Ph.D., M.P.H., Ward Ortmann, B.S., Sophie Garnier, Ph.D., Annette T. Lee, Ph.D., Sharon A. Chung, M.D., Ricardo C. Ferreira, B.S., P.V. Krishna Pant, Ph.D., Dennis G. Ballinger, Ph.D., Roman Kosoy, Ph.D., F. Yesim Demirci, M.D., M. Ilyas Kamboh, Ph.D., Amy H. Kao, M.D., M.P.H., Chao Tian, B.S., Iva Gunnarsson, M.D., Ph.D., Anders A. Bengtsson, M.D., Ph.D., Solbritt Rantapää-Dahlqvist, M.D., Ph.D., Michelle Petri, M.D., Susan Manzi, M.D., M.P.H., Michael F. Seldin, M.D., Ph.D., Lars Rönnblom, M.D., Ph.D., Ann-Christine Syvänen, Ph.D., Lindsey A. Criswell, M.D., M.P.H., Peter K. Gregersen, M.D., and Timothy W. Behrens, M.D.
Background Systemic lupus erythematosus (SLE) is a clinicallyheterogeneous disease in which the risk of disease is influencedby complex genetic and environmental contributions. Allelesof HLA-DRB1, IRF5, and STAT4 are established susceptibilitygenes; there is strong evidence for the existence of additionalrisk loci.
Methods We genotyped more than 500,000 single-nucleotide polymorphisms(SNPs) in DNA samples from 1311 case subjects with SLE and 1783control subjects; all subjects were North Americans of Europeandescent. Genotypes from 1557 additional control subjects wereobtained from public data repositories. We measured the associationbetween the SNPs and SLE after applying strict quality-controlfilters to reduce technical artifacts and to correct for thepresence of population stratification. Replication of the toploci was performed in 793 case subjects and 857 control subjectsfrom Sweden.
Results Genetic variation in the region upstream from the transcriptioninitiation site of the gene encoding B lymphoid tyrosine kinase(BLK) and C8orf13 (chromosome 8p23.1) was associated with diseaserisk in both the U.S. and Swedish case–control series(rs13277113; odds ratio, 1.39; P=1x10–10) and also withaltered levels of messenger RNA in B-cell lines. In addition,variants on chromosome 16p11.22, near the genes encoding integrinalpha M (ITGAM, or CD11b) and integrin alpha X (ITGAX), wereassociated with SLE in the combined sample (rs11574637; oddsratio, 1.33; P=3x10–11).
Conclusions We identified and then confirmed through replicationtwo new genetic loci for SLE: a promoter-region allele associatedwith reduced expression of BLK and increased expression of C8orf13and variants in the ITGAM–ITGAX region.
Source Information
The authors' affiliations are listed in the Appendix. Drs. Hom and Graham contributed equally to this article. This article (10.1056/NEJMoa0707865) was published at www.nejm.org on January 20, 2008.
Address reprint requests to Dr. Behrens at Genentech, 1 DNA Way, 45-3B, South San Francisco, CA 94080, or at behrens.timothy{at}gene.com.
Rhodes, B., Vyse, T. J.
(2008). The genetics of SLE: an update in the light of genome-wide association studies. Rheumatology (Oxford)
47: 1603-1611
[Abstract][Full Text]
Lettre, G., Rioux, J. D.
(2008). Autoimmune diseases: insights from genome-wide association studies. Hum Mol Genet
17: R116-R121
[Abstract][Full Text]
Tian, C., Gregersen, P. K., Seldin, M. F.
(2008). Accounting for ancestry: population substructure and genome-wide association studies. Hum Mol Genet
17: R143-R150
[Abstract][Full Text]
Sigurdsson, S., Nordmark, G., Garnier, S., Grundberg, E., Kwan, T., Nilsson, O., Eloranta, M.-L., Gunnarsson, I., Svenungsson, E., Sturfelt, G., Bengtsson, A. A., Jonsen, A., Truedsson, L., Rantapaa-Dahlqvist, S., Eriksson, C., Alm, G., Goring, H. H.H., Pastinen, T., Syvanen, A.-C., Ronnblom, L.
(2008). A risk haplotype of STAT4 for systemic lupus erythematosus is over-expressed, correlates with anti-dsDNA and shows additive effects with two risk alleles of IRF5. Hum Mol Genet
17: 2868-2876
[Abstract][Full Text]
Cimaz, R., Guerrini, R.
(2008). Epilepsy in lupus. Lupus
17: 777-779
Behrens, E. M., Ning, Y., Muvarak, N., Zoltick, P. W., Flake, A. W., Gallucci, S.
(2008). Apoptotic Cell-Mediated Immunoregulation of Dendritic Cells Does Not Require iC3b Opsonization. J. Immunol.
181: 3018-3026
[Abstract][Full Text]
Lech, M., Kulkarni, O. P., Pfeiffer, S., Savarese, E., Krug, A., Garlanda, C., Mantovani, A., Anders, H.-J.
(2008). Tir8/Sigirr prevents murine lupus by suppressing the immunostimulatory effects of lupus autoantigens. JEM
205: 1879-1888
[Abstract][Full Text]
Huang, X., Moore, D. J., Ketchum, R. J., Nunemaker, C. S., Kovatchev, B., McCall, A. L., Brayman, K. L.
(2008). Resolving the Conundrum of Islet Transplantation by Linking Metabolic Dysregulation, Inflammation, and Immune Regulation. Endocr. Rev.
29: 603-630
[Abstract][Full Text]
Grant, S. F. A., Hakonarson, H.
(2008). Microarray Technology and Applications in the Arena of Genome-Wide Association. Clin. Chem.
54: 1116-1124
[Abstract][Full Text]
Crow, M. K.
(2008). Collaboration, Genetic Associations, and Lupus Erythematosus. NEJM
358: 956-961
[Full Text]
(2008). Unraveling the Genetic Predisposition to Systemic Lupus Erythematosus. Journal Watch Dermatology
2008: 1-1
[Full Text]
Previous
